Parenteral composition to reduce duration of local anesthesia



PARENTERAL COMPOSITION TO REDUCE DURATION OF LOCAL ANESTHESIA Froilan P. Luduena, Albany, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware N Drawing. Application July 26, 1955 Serial No. 524,595

Claims. (Cl. 167--65) This invention relates to a physiologically compatible solution adapted for parenteral administration to reduce the duration of vasoconstrictor-potentiated local anesthesia, comprising as essential ingredients an aminomethylbenzodioxan, adenosine and water.

In order to obtain rapid, intense and localized anesthesia, it has long been customary to administer with the local anesthetic a vasoconstricting agent such as epinephrine, arterenol, phenylephrine or nordefrin. The vasoconstrictor serves to inhibit the otherwise rapid systemic absorption of the local anesthetic.

A disturbing disadvantage of such local anesthetic solutions, however, is that complete or partial anesthesia persists too long after completion of the operative procedure for which it is needed. This unnecessary terminal anesthesia, for instance in dentistry, results in discomfort and annoyance to the patient in the form of an undesirable residual numbness of lips, cheeks, and sometimes also of the tongue. This undesirably long duration of anesthesia lasts from about two to four hours, or longer in some instances, the time depending on the particular anesthetic solution used.

The duration of anesthesia for a given anesthetic solution depends on the properties of each of the active ingredients, that is, the anesthetic agent and the vasoconstricter. Attempts to decrease the duration of anesthesia have been made by searching for more potent, shorteracting anesthetics. Limited success has been obtained in this direction by the introduction within the last decade of highly potent, short-acting anesthetics such as lidocaine and propoxycaine. However, use of these newer local anesthetics in vasoconstrictor-potentiated anesthetic solutions still results in a duration of anesthesia of about two to two and one-half hours or more. Attempts also have been made to decrease the duration of anesthesia by using an anesthetic solution having no vasoconstrictor; however, such apreparation has neither the required depth of anesthesia nor the necessary duration of anesthesia.

I have now found that this undesirably long duration of terminal anesthesia can be reduced greatly by administering parenterally at the site of the anesthetic injection a physiologically compatible solution comprising an aminomethylbenzodioxan and adenosine.

The effectiveness of my solution has been demonstrated by experimental tests in animals (guinea pigs) and confirmed in human subjects. My solution is administered by injection in the same location about fifteen to thirty minutes after the injection of the anesthetic solution or after the operation has been completed. In human patients, symptoms of anesthesia diminish rapidly almost immediately and disappear almost completely within about forty to ninety minutes.

By the term aminomethylbenzodioxan as used in this at a minimum effective level.

"2,919,228 Patented Dec. 29, 1959 "ice results with the piperidino compound, piperoxan hydrochloride, but, for instance, the diethylamino compound, prosympal hydrochloride, can also be used.

The adenosine can be employed either as the simple adenine-riboside, or as one of the phosphate esters thereof such as the monophosphate or triphosphate.

To be physiologically compatible my new compositions are formulated to be reasonably near the osmotic pressure and pH of blood, and desirably the solutions should contain a butler. Since the aminomethylbenzodi oxan is most soluble and stable at acidic pHs, a practical compromise must be efiected. The operable pH range is about 3.5 to 7, with solutions having values within this range being stable and effective. Bufiering agents can be utilized to adjust and maintain the pH within the operable range or within the preferred range of about 4 to 6.

As with the concentrations of the anesthetic agent and the vasoconstrictor of injectable local anesthetic solutions, the concentrations of the aminomethylbenzodioxan and adenosine of my solution should be kept preferably Preferred embodiments of my invention contain about 0.01 to 0.50% (weight per volume) of piperoxan, preferably in the form of its hydrochloride, about 0.10 to 0.30% (weight per volume) of adenosine, and enough sodium chloride to make the solution isotonic. Optimum concentrations are about 0.05 to 0.10% of piperoxan and about 0.20% adenosine.

The following examples will illustrate the specific embodiments of my invention without, however, limiting it thereto. All percentages given hereinbelow and in the claims are in terms of weight per volume, e.g., grams per cc.

Example 1 Solutions were prepared by mixing well the following ingredients:

Piperoxan hydrochloride ..g 0. 050 0, 025 Adenosine g. 0. 20 0. 20 Sodium chloride g 0. 0. s5 Distilled water, q.s. ad "00.. 100.00 100.00

Using this method, the times necessary to reduce anesthesia to three-fourths, one-half, and one-fourth of the maximal value were determined. The relative effectiveness of solutions of varied composition was determined in this manner. The following table shows the relative efifectiveness of my above solution 1B (experiment 11) and a solution containing only sodium chloride (experiment 1). The anesthetic solution used (0.25 cc. for each injection) contained propoxycaiue hydrochloride (0.4%),

procaine hydrochloride (2.0%) and levo-arterenol 1 7 3 0,000)

Average Duration Second Injection 1 of Anesthesia After Second In- Volume jection (minutes) Experi- Injected ment (cc) 4 Cone. Percent Anesthesia Solution Percent wt./vol.

I b aline fi6l & r &5 0.50 117 140 180 II iperoxan an 0.

Adenosine 1 0. 20 l 23 26 30 Solutions of my invention were prepared by mixing well the following ingredients:

Piperoxau H01 g 1.00 1. 00 Adenosine -g. 4. 00 4. 00 Sodium Lactate cc 400 720 Lactic Acid cc 400 80 Distilled water, q.s. ad--- co.. 2, 000 2.000 pH when compounded 4. 4. 85

Solutions 2A and 2B were filtered into 2.2 cc. cartridges through a sterilizing filter.

Solution 2B was administered to human subjects to establish its effectiveness in shortening the duration of dental anesthesia as follows: Four subjects were given bilateral mandibular injections of 2.0 cc. each of a local anesthetic solution containing propoxycaine hydrochloride (0.4%), procaine hydrochloride (2.0%) and 3,4-dihydroxynorephedrine hydrochloride (1110,000), each injection being made at a rate of 1 cc. per minute. A full cartridge of solution 2B (2.2 cc.) was then injected in each subject in the same location, on the right side only, about fifteen minutes after the onset of symptoms of anesthesia. After the injection of solution 213, the symptoms of anesthesia started to regress rapidly and Within thirty-eight minutes from the time solution 213 was injected, sensations had returned to the teeth on the right side in all cases. All symptoms of anesthesia ceased in the right side after about ninety-six minutes. In the left side, sensation returned to the teeth after about one hundred and fifty minutes and all symptoms disappeared after about one hundred and ninety-five minutes. No unpleasant local symptoms were reported during or after the second injection. Also, no systemic effects and no postoperative signs of irritation were observed.

4 Example 3 Solutions within the scope of my invention having pH values between about 4.0 and about 5.0 were prepared by mixing well the following ingredients:

Piperoxan Hydrochloride g.. 0.05 0.05 0.05 Adenosine g- 0. 20 0. 20 0. 20 Citric Acid--- -g 0. 4.0 O. 40 0.20 Sodium Citrate .g.. 0.40 0.60 0. Sodium Chloride g 0. 60 0. 54 0.51 Distilled Water, q.s. ad .00.. 100.00 100.00 100.00 pln d. 05 4. 45 5. 0

Solutions 3A, 3B and 3C were filled into 2 cc. flint ampuls and in each case half the batch was heated at 121 C. for fifteen minutes and the other half was not heated.

These solutions showed excellent stability on storage,- even at 37 C.

Example 4 Solutions having pH values between about 5.5 and about 7.0 were prepared by mixing well the following ingredients Piperoxan HO] 0. 05 0. 05 0. 05 0.05 Adenosine..- 0. 20 0. 20 0. 20 0.20 lttz iiPOl. 0.20 0. 45 0. 75 0. 90 N ZiHgPOi-HzO 0. S0 0. 30 0.20 0.10 Sodium Ohlo11de 0. 39 0. 55 O. 52 0. 53 Distilled Water, (1.5. ad. 100. 00 100.00 100.00 100.00 pH 5. 5 6.0 6.5 7. 0

Solutions 4A, 4B, 4C and 4D were filled into 2 cc. flint ampuls and in each case half the batch was heated at 121 C. for fifteen minutes and the other half was not heated. These solutions showed excellent stability on storage even at 37 C.

Example 5 Solutions were prepared by mixing well the following ingredients:

Piperoran hydrochloride g 0. 025 0.025 Adenosinc-einonophosphate g 0. 20 Adenosine trinh nh v 0. 10 Sodium chloride .g 0. 0. 85 Distilled water, q.s. ad ce 100.00 100.00

The efiectiven'ess of solutions 5A and 5B in reducing the duration of anesthesia produced by the injection of a vasoconstrictor-potentiated local anesthetic solution was determined using guinea pigs following the procedure given in Example 1. The results are presented in the following table:

' Administered intrndermally.

b Accumulation of data from a number guinea pigs.

0.85% NaCl.

of experiments involving 56 I claim:

1. A physiologically compatible solution adapted for parenteral administration to reduce the duration of vasoconstrictor-potentiated local anesthesia comprising as essential ingredients about 0.01 to 0.50% of an aminomethylbenzodioxan selected from the group consisting of 2-( l-piperidylmethyl) -1,4-benzodioxan, Z-(diethylaminomethyl)-l,4-benzodioxan and acid-addition salts thereof, about 0.10 to 0.30% of a compound selected from the group consisting of adenosine and a monophosphate ester thereof, and water, said solution having a pH range of about 3.5 to 7.

2. A physiologically compatible solution adapted for parenteral administration to reduce the duration of vasoconstrictor-potentiated local anesthesia comprising about 0.01 to 0.50% of piperoxan hydrochloride, about 0.10 to 0.30% of adenosine and water, said solution having a pH range of about 3.5 to 7.

3. A physiologically compatible solution adapted for parenteral administration to reduce the duration of vasoconstrictor-potentiated local anesthesia comprising about 0.05 to 0.10% of piperoxan hydrochloride, about 0.20% of adenosine, water and enough sodium chloride to make the solution isotonic, said solution having a pH range of about 3.5 to 7.

4. A physiologically compatible solution adapted for parenteral administration to reduce the duration of vaso constrictor-potentiated local anesthesia comprising about 0.05% of piperoxan hydrochloride, about 0.20% of adenosine, water, a buflering agent to maintain the pH Within the range of about 4.0 to about 6.0. and enough sodium chloride to make the solution isotonic.

5. A physiologically compatible solution adapted for parenteral administration to reduce the duration of vasoconstrictor-potentiated local anesthesia comprising about 0.01 to 0.50% of piperoxan hydrochloride, about 0.10 to 0.30% of adenosine, water and a buffering agent to maintain the pH within the range of about 3.5 to 7.

References Cited in the file of this patent Sollmann: 8th ed., W. B. Saunders, 1957, p. 516. Goodman et a1.: Pharmacol. Basis of Therapeutics, 1st

ed., Macmillan Co., N.Y.C., p. 289.

tatif, Karger, Basil, 1948, p. 271. 

1. A PHYSIOLOGICALLY COMPATIBLE SOLUTION ADAPTED FOR PARENTERAL ADMINSITRATION TO REDUCE THE DURATION OF VASOCONTRICTOR-POTENTIATED LOCAL ANESTHESIA COMPRISING AS ESSENTIAL INGREDIENTS ABOUT 0.01 TO 0.50% OF AN AMINOMETHYLBENODIOXAN SELECTED FROM THE GROUP CONSISTING OF 2-(1-PIPERIDYLMETHYL)-1,4-BENZODIOXAN, 2-(DIETHLAMINOMETHYL)-1,4-BENZODIOXAN AND ACID-ADDITION SALTS THEREOF ABOUT 0.10 TO 0.30% OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF ADENOSINE AND A MONOPHOSPHATE ESTER THEREOF, AND WATER, SAID SOLUTION HAVING A PH RANGE OF ABOUT 3.5 TO 7 